Dutton Amanda, Woodman Ciaran B, Chukwuma Marilyn B, Last James I K, Wei Wenbin, Vockerodt Martina, Baumforth Karl R N, Flavell Joanne R, Rowe Martin, Taylor A Malcolm R, Young Lawrence S, Murray Paul G
Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, Edgbaston, United Kingdom.
Blood. 2007 Mar 15;109(6):2597-603. doi: 10.1182/blood-2006-05-020545. Epub 2006 Dec 5.
Polycomb group (PcG) proteins are chromatin modifiers that are necessary for the maintenance and renewal of embryonic and adult stem cells. However, overexpression of the PcG protein, Bmi-1, causes lymphoma in transgenic mice. We show that Bmi-1 is up-regulated in Hodgkin lymphoma (HL) cells by the Epstein-Barr virus (EBV) oncogene latent membrane protein-1 (LMP1) and that this up-regulation is mediated by NF-kappaB signaling. We also show that Bmi-1 is up-regulated by NF-kappaB in EBV-negative HL cells. Down-regulation of LMP1 and Bmi-1 decreased the survival of HL cells, suggesting that Bmi-1 may mediate the prosurvival effects of LMP1-induced NF-kappaB signaling in HL cells. Transcriptional targets of Bmi-1 were identified after its knockdown in an HL cell line. We show here that Bmi-1 and LMP1 down-regulate the ataxia telangiectasia-mutated (ATM) tumor suppressor and conclude that Bmi-1 contributes to LMP1-induced oncogenesis in HL.
多梳蛋白家族（PcG）蛋白是染色质修饰因子，对胚胎干细胞和成年干细胞的维持与更新至关重要。然而，PcG蛋白Bmi-1的过表达会在转基因小鼠中引发淋巴瘤。我们发现，在霍奇金淋巴瘤（HL）细胞中，爱泼斯坦-巴尔病毒（EBV）致癌基因潜伏膜蛋白1（LMP1）可上调Bmi-1的表达，且这种上调是由核因子κB（NF-κB）信号通路介导的。我们还发现，在EBV阴性的HL细胞中，NF-κB也可上调Bmi-1的表达。LMP1和Bmi-1的下调降低了HL细胞的存活率，这表明Bmi-1可能介导了LMP1诱导的NF-κB信号通路在HL细胞中的促存活作用。在一个HL细胞系中敲低Bmi-1后，我们鉴定出了其转录靶点。我们在此表明，Bmi-1和LMP1下调了共济失调毛细血管扩张症突变（ATM）肿瘤抑制因子，并得出结论，Bmi-1参与了LMP1诱导的HL肿瘤发生。
